Engineered nano scale formulation strategies to augment efficiency of nutraceuticals

Journal of Functional Foods 62 (2019) 103554

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Engineered nano scale formulation strategies to augment efficiency of nutraceuticals

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Asad Ali, Usama Ahmad , Juber Akhtar, Badruddeen, Mohd Muazzam Khan Faculty of Pharmacy, Integral University, Lucknow, India

A R T I C LE I N FO

A B S T R A C T

Keywords: Nutraceuticals Bioactives Bioavailability Solubility Nanotechnology Delivery systems

Nutraceuticals have been widely explored for promoting health outcomes and in management of various diseases. They are considered to be neutral and safe and are extensively used to promote overall health. They play a vital role in modifying and maintaining normal body physiological functions. However, the bioactives present in nutraceuticals are unable to achieve their potential outcomes due to limited aqueous solubility leading to poor bioavailability profile and interaction with gastro-intestinal fluids. Majority of conventional products in market are unable to show their therapeutic outcome. Nanotechnology has tremendous potential to revolutionize the nutraceutical market. Recent progress in field of nutraceutical delivery has incorporated nanotechnology to overcome the drawbacks accompanying nutraceuticals. This review focuses on issues associated with nutraceuticals and various nanoscale formulation approaches like liposomes, nanoemulsions, nanocrystals, lipid and polymeric nanoparticles to obtain an insight to recent developments in nutraceuticals segment.

1. Introduction Nanotechnology is moving out of the dominion of science fiction into our buildings, drugs, clothing, cosmetics, and even jolting into our foods, beverages, and dietary supplements. According to National Nanotechnology Initiative (NNI), nanotechnology has been broadly defined as the science and technology involved in the design, synthesis, characterization, and application of materials and devices with at least one of the dimensions on the nanoscale (usually in the range of 1–100 nm) (NNI, 2005). Nanotechnology has vast applications in food industry. It deals with size range of 10-9 m and at this size particles exhibit unique properties which changes the pharmacokinetics of the molecules and its subsequent effects. A nutrient is anything that nourishes and is essential for a living being. The word nutrient has historical background and is derived from Latin word ‘nutrire’ meaning ‘to feed’, although the word first started out in 1965 as an adjective meaning ‘providing nourishment’. The term nutraceuticals means, “a food that has the required nutrient along with therapeutic effect.” The term nutraceuticals was first introduced by the chairperson and founder of “Foundation for Innovation in Medicine” by Mr. Stephen DeFelice in 1989 (Brower, 1998; Maddi, Aragade, Digge, & Nitalikar, 2007).

Nutraceuticals are products that provide essential components to the body and prevent disease. It is a requirement beyond the basic nutrition which we get from our daily meals. It may comprise of dietary supplements, products of plant origin, nutrients that are isolated from mixture, genetically engineered food and products which are processed like beverages, cereals and soups, etc. (Dureja, Kaushik, & Kumar, 2003). At present a lot of conventional nutraceutical products are available in the market ranging from simple low cost products for daily use to high cost combinations prescribed in ailments. Population is spending more money on buying healthy and organic food in order to avoid illness which in turn is boosting the overall nutraceuticals market worldwide (Nelson, 1999). The global market of nutraceuticals was at US$165.62 billion in 2014. From 2015 to 2021 it is growing at a CAGR (Compound Annual Growth Rate) of 7.3% and by the end of 2021 the market is expected to reach US$278.96 billion according to the report published by transparency market research in September 2015 ((Nutraceuticals Product Market, 2015). Compound annual growth rate (CAGR) is a business and investing specific term for the geometric progression ratio that provides a constant rate of return over the time period. CAGR is not an accounting term, but it is often used to describe some element of the business, for example revenue, units delivered, registered users, etc. It is particularly useful to compare growth rates

Abbreviations: GSK, GlaxoSmithKline; CAGR, Compound Annual Growth Rate; GIT, gastro intestinal tract; PEG, polyethylene glycol; SAILA, Supercritical Assisted Injection in a Liquid Antisolvent; HPH, High Pressure Homogenization; SLNs, solid-lipid nanoparticles; NLCs, nanostructured lipid carriers; HPMC, hydroxypropyl methycellulose; PLGA, poly lactic-co-glycolic acid ⁎ Corresponding author at: Faculty of Pharmacy, Integral University, Lucknow 226026, India. E-mail address: [email protected] (U. Ahmad). https://doi.org/10.1016/j.jff.2019.103554 Received 8 April 2019; Received in revised form 16 June 2019; Accepted 2 September 2019 1756-4646/ © 2019 Elsevier Ltd. All rights reserved.

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Enzymes increases the rate of metabolic activity occuring inside the cells. Various problems can be treated by enzyme supplements like constipation, diarrhoea, GERD (gastroesophageal reflux disease), ulcerative colitis. Rare diseases like Hunter syndrome, Gaucher disease, Pompe disease, and Fabry disease can be treated by enzyme therapy. Diabetic patient could be treated with enzymes. From economical point of view microbial sources of enzyme are much preferred over plant and animal sources as they are much cheaper (Chanda, Tiwari, Kumar, & Singh, 2019). (ii) Probiotic microorganisms: The term “Probiotic” was coined by Metchnikoff. The probiotic microorganisms has a vital position in medical field when it comes to process such as metabolism and absorption as it makes the intestine more favourable to these processes. Probiotics act by eradicating toxic flora that houses inside the intestine. For example useful consumption of Bacillus bulgaricus (Holzapfel, Haberer, Geisen, Björkroth, & Schillinger, 2001). Ailments of the human body can be treated by different probiotics product present in the market which has sufficient nutrient to fight various pathogen that causes discomfort in human body. The probiotics act by making the epithelial cells of the intestine more grounded thereby aiding the probiotics products for better retention, which is the need of the body. Probiotics are also helpful in people suffering from lactose intolerance as they help the sufferer by production of related enzyme ß-galactosidase which hydrolyzes lactose into its sugar components (Pineiro & Stanton, 2007).

from various data sets of common domain such as revenue growth of companies in the same industry or sector. However, the problem with vast majority of these existing nutraceuticals is the lack of efficay invivo. These lipophilic compounds have been limited in their application to food system due to their extremely poor aqueous solubility, low oral bioavailability, g.i.t degradation, easy to oxidize, and immiscible feature with other major hydrophilic compounds (Ezhilarasi, Karthik, Chhanwal, & Anandharamakrishnan, 2013). According to the Biopharmaceutics Classification System (BCS) most functional foods could be classified into four different systems depending on their solubility and permeability. Most lipophilic components belong to class II or class IV in which low solubility is the major problem (Velikov & Pelan, 2008). Low solubility and poor adsorption of bioactive compounds would be also closely related to the low oral bioavailability due to lower stability of compounds and poor hepatic first pass metabolism (Oehlke et al., 2014; Patel & Velikov, 2011; Velikov & Pelan, 2008). Lipid-based delivery systems have been used to increase the bioavailability of BCS Class II drugs because they are broken down into mixed micelles in the small intestine, which increases the solubility of the drug in the intestinal fluids (Williams et al., 2013). Nanotechnology’s application in nutrition and food industry is to fabricate or formulate food ingredients with novelty which has marked enhancement in its solubility, stability towards heat and light, better oral bioavailability and much pronounced physiological performance. Nano-carrier systems utilizes cores that may be liquid (emulsions and microemulsions), solid (solid lipid nanoparticles-SLNs), or a mix of solid and liquid domains (nanostructured lipid carriers-NLCs). Particles for encapsulation of hydrophilic ones are composed of an aqueous core, delineated from the surrounding continuous phase by a shell. These include nanohydrogels, liposomes and colloidosomes. In both categories, the nanocarriers are stabilized by either emulsifying molecules (emulsions) or by colloidal particles (Pickering emulsions) (Dan, 2016). All these have been widely exploited for effective delivery of lipophilic agents. Due to their extremely small size, nanocarriers have shown many advantages such as improvement of the aqueous solubility, enhancement of residence time in gastrointestinal (GI) tract regions, better physicochemical stability in GI tract, increase the intestinal permeation, controlled release in GI tract, intracellular delivery, and transcellular delivery (Oehlke et al., 2014). So it becomes essential to design maps for a better nutraceutical industry by merging it with nanotechnology. Role of nutraceuticals can be more glorified by using nanotechnology which will definitely ensure better results than the traditional products available in the market. Owing to these nanotech advantages, an attempt has been made through this extensive review work to gain an insight or status of how engineered nanoscale formulation strategies are enabling effective delivery of nutraceuticals by minimizing their above mentioned limitations and improving the overall efficiency in-vivo.

On the basis of Chemical Constituent: (i) Phytochemicals: Classification of this class is done on the basis of phytochemical present. Flavonoids are secondary metabolites, present in many plants and has been clinically proven for preventing diseases like heart problems, diabetes, kidney problems by its antioxidant potential (Ehrlich, 2009). Legumes like chickpeas and soybeans contains noncarotenoids which prevent cholesterol and has the potential to kill carcinogenic cells. Likewise anticancer activity property is also possessed by carotenoids which are present in vegetables. They also increases the immune system potential of an individual (Chanda et al., 2019). Free radicals are produced as a product of metabolism of carbohydrate, fat, protein. These free radicals detoriates the cell of human body. One of the class of metabolites are the phenolic acid found in citrus fruits and red wine which has the property to destroy free radicals. This class of phytochemicals also has antitumor and anticancer property also (Chanda et al., 2019). Classical example is of tumeric (curcumin), used as phytochemical in many kitchen (Chanda et al., 2019) and has antiinflammatory, antioxidant, wound healing, anticancer and many more properties. (ii) Nutrient: Metabolic reactions occuring inside the human body are very much influenced by primary metabolite such as vitamins, amino acids, fatty acids as they have well defined functions to play in these metabolic reactions. Diseases related to heart, lung, kidney and other organs can be cured with product which are of plant and animal origin along with vitamin and may have several health benefit on the body. Maintenance of rhythm of heart muscles, transmission through neurons, providing strenght to bones and muscles, treating low heamoglobin count and many more ailments could be treated by natual products of plant and animal origin. For example reduction in cholesterol level in arteries and better functioning of the brain are well contributed effects of fatty acid, omega-3 PUFAs which is found in salmon. (iii) Herbal: Many chronic disorder can be treated by the combination of herbal products with nurtraceutical. Antiarthritic, analgesic, astringent, antipyretic, anti-inflammatory properties are possessed

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1.1. Classification of nutraceuticals Nutraceuticals could be classified into many types, however broadly they are categozied on the basis of food valaibility, chemical nature and mechanism of action of active component. These broad categories are further classified into various sub classes and are presented in Fig. 1. Traditional Nutraceuticals are those which are obtained directly from nature and are used as such without any change in their form. Different constituents are available and used for various health related benefits like omega-3 fatty acid present in cod liver oil, saponin in soy, lycopene in tomatoes and its product etc. Traditional nutraceuticals can be futher divided into: (i) Nutraceutical enzymes (ii) Probiotic microorganisms (iii) Chemical Constituents (iv) Phytochemicals (v) Nutrients and (vi) Herbal (i) Nutraceutical enzymes: Enzymes are biocatalyst which are proteinous in nature, specific in action and are produced by cells of body. 2

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Fig. 1. Nutraceuticals classification.

2. Problems associated with nutraceuticals:

by salicin found in willow bark (Salix nigra). Antipyretic, carminative, diuretic effect is shown by psoralen found in parsley (Petroselinum crispum) which falls under the category of flavonoids. Cold and flu can easily be cured by various terpenoids especially menthol, a bioactive constituent present in Peppermint (Mentha piperita). Relaxing stress, lowering blood pressure and treating lung disorder such asthma are some of the medicinal effect of tannin contents of lavender (Lavandula angustifolia) (Ehrlich, 2008).

Everything we eat has an impact on our life. The constituents present in food have ability to alter biological processes only if they are able to reach the systemic circulation. Majority of the constituents used in nutraceuticals are derived from natural sources and the common problems associated with them is low aqueous solubility and bioavailability.

Nontraditional Nutraceuticals: These are biotechnologically designed crops or food that that have much higher amount of nutrient when compared to normal crops or food. They can be classified as:

2.1. Issues of solubility and bioavailability in nutraceuticals

(i) Recombinant Nutraceuticals: Biotechnology tools have been well applied through a fermentation process in various food materials such as cheese and bread to extract the enzyme useful for providing necessary nutrients at an optimum level. (ii) Fortified Nutraceuticals: In this type of nutraceutical compatible nutrients are added to the main ingredients such as flour fortified with calcium, milk fortified with cholecalciferol inorder to treat deficiency of vitamin D, minerals added to cereals, etc. (Casey, Slawson, & Neal, 2010). Detailed classification of nutraceuticals is represented in Fig. 1.

The fate of orally ingested bioactive in body depends upon its contact with gastro-intestinal fluid. The maximum proportion in gastrointestinal fluid is of water and if the drug, vitamin, bioactive or any other nutraceutical is poorly aqueous soluble then the objective of administering it has no significance. Infact most of nutraceuticals fall under BCS Class II and Class IV which represents low aqueous solubility and low permeability across membrane. Aqueous solubility of bioactives is directly related to release behavior which in turn is correlated with bioavailability. Some of the problems associated with commonly used nutraceuticals is described below. Curcumin is a lipophilic compound, practically insoluble in water, with its solubility in aqueous solution (at pH 5.0) as only 11 ng/mL (Hu et al., 2015). The lipophilic characteristic of curcumin (log P of 3.29), 3

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Table 1 Common bioactive nutraceuticals, their source, limitations and benefits. Nutraceutical class/components with examples

Food source

Health benefits

Drawbacks

References

Salmon, Sardines, Trout, Tuna Eggs, Milk, Yoghurt, Margarine Cereal, Flaxseed, Oatmeal Canola oil, Cod liver oil, Mustard oil, Soybean oil etc

Lowers risk of heart disease

Low water solubility Poor chemical stability High lipid oxidation

Salvia-Trujillo, Decker, & McClements, 2016; Walker, Decker, & McClements, 2015

From seeds of silybum marianum plant

Antioxidant Free radical scavanger Hepatoprotective

Low water solubility Poor chemical stability Gastric degradation Poor bioavailability

Ahmad et al., 2015

Carrot, tomato, yellow squash, broccoli, citrus fruits, berries, cantaloupe, pumpkin, sweet potatoes, paprika, green vegetables

Antioxidant Anti-aging Preventing heart disease

Low water solubility Poor bioavailability Poor oxidation stability

Ames, Shigenaga, & Hagen, 1993; Paliyath et al., 2011; Kohlmeier & Hastings, 1995; Stegemann, Leveiller, Franchi, De Jong, & Lindén, 2007; Rissanen et al., 2003

Flavanone Naringenin

Grape fruits, oranges, tomatoes

Antioxidant Anti-inflammatory Hepatoprotective

Low water solubility Low bioavailability

Yen, Wu, Lin, Cham, & Lin, 2009

Carotenoids Lycopene

Tomato and its products

Antioxidant Anti-prostate

Low water solubility Poor bioavailability

Paliyath et al., 2011

Spinach, banana, egg yolk, green vegetables

Antioxidant Improve vision

Low water solubility Poor bioavailability

Yoo, Baskaran, & Yoo, 2013

Isoflavonoid C-glycosides Puerarin

Kudzu roots

Antioxidant Hypocholesterolemic effects

Poor water solubility Poor bioavailability

Chung et al., 2008; Wang et al., 2013

Stilbenoid Resveratrol

Grapes (skins), red wine

Decrease LDL and increase HDL Antioxidant Anticancer

Low water solubility Poor bioavailability

Augustin, Sanguansri, & Lockett, 2013

White tea, Green tea, Black tea

Antioxidant Atherosclerosis Blood sugar control

Poor bioavailability

Nagle, Ferreira, & Zhou, 2006; Shpigelman, Israeli, & Livney, 2010

Red grapes, citrus fruit, onion, apple skin, berries, tea, broccoli

Lower blood lipid Anti-inflammatory Antioxidant

Low water solubility Poor bioavailability

Patel, Heussen, Hazekamp, Drost, & Velikov, 2012

Phenylpropanoid Capsaicin

Chilli pepers

Anti-inflammatory Induces apoptosis in many cancer cell types, including stomach, colon, liver breast, prostate cancer and lukemia. Neurophysiological effects

Low water solubility

Mori et al., 2006; Yang et al., 2009

Curcuminoids Curcumin

Turmeric

Anti-inflammatory Antioxidant Anticancer Protective agent against several chronic diseases, including, HIV-infection, neurological, cardio-vascular and skin diseases.

Low solubilityPoor bioavailability

Hatcher, Planalp, Cho, Torti, & Torti, 2008; Paramera, Konteles, & Karathanos, 2011

Ubiquinone Coenzyme Q10

Meat, seafoods

Antioxidant

Water insoluble Poor bioavailability

Zaki, 2014

Fatty acid Omega-3 ALA (alpha-linolenic acid), DHA (docosahexaenoic acid), and EPA (eicosapentaenoic acid)

Flavano-lignan Silymarin

Carotenoids β-carotene α-carotene

Oxygenated carotenoid Lutein

Gallate ester Epigallocatechin-3-gallate (ECGC) Flavonols Quercitin

(continued on next page) 4

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Table 1 (continued) Nutraceutical class/components with examples

Food source

Health benefits

Drawbacks

References

Dairy products such as milk, cheese, butter, yogurt, fish liver oils, eggs, chicken, liver, beef, kidney, mangoes, peaches, apricots, cantaloupe, winter squash, leafy vegetables, pumpkin, carrots and sweet potatoes etc

Antioxidant Promotes Immune health Anti-ageing properties

Water insoluble Poor bioavailability

Pitha, 1981

Vitamin D (Cholecalciferol)

Dairy products, cereals, liver, eggs, cod liver oil etc

Calcium metabolism Absorption of phosphorus and calcium

Water insoluble Poor bioavailability

Pitha, 1981

Vitamin E (Tocopherol)

Hazelnuts, Brazil nuts, walnuts, almonds, sunflower seeds, Green leafy vegetables, liver, fortified cereals, mangoes, avocados, corn, broccoli, spinach etc

Antioxidant Maintains cholesterol level Reduce risk of prostate and breast cancer

Water insoluble Poor bioavailability

Dubbs & Gupta, 1998; Pitha, 1981; Gong et al., 2012

Vitamin K (Phytonadione)

Leafy green vegetables, soybeans, dairy products, meats, legumes

Helps in blood clotting Prevents kidney stones Regulate calcium levels

Water insoluble Poor bioavailability

Dubbs & Gupta, 1998; Pitha, 1981

Micronutrients Oil soluble Vitamins Vitamin A (Retinol)

salt and phospholipids etc. which are synthesized by the body itself, (ii) Proteins, dietary fibers, surfactants etc. can be the other source of these gastro-intestinal fluid constituents. In such circumstances, the constituents present in nutraceuticals are likely to form complexes which in turn may decrease the availability of constituents in systemic circulation (McClements et al., 2015). For example, low bioavailability is reported for calcium ions that are positively charged and when they interact with long chain of saturated fatty acid which have negative charge, in the gastro-intestinal fluids (Wydro, Krajewska, & Hac-Wydro, 2007). Many bioactive drugs have reduced bioavailability due the complex molecular interaction that occurs in the gastro-intestinal fluid. Further absorption and digestion of many mineral ions can be altered because of the chelating agents present in the gastro-intestinal fluid. G.I.T has many charged species like enzymes, bile salts, phospholipids etc, to which proteins (biopolymer, electrically charged) may get attached by electrostatic interactions (Wydro et al., 2007). Other factors, such as pH variations, ionic strength, enzymatic degradations, and mechanistic motilities, potentially contribute to the degradation of nutraceuticals. One good example of a bioactive which suffers in-vivo due to instability caused by g.i.t contents is lutein. Lutein is part of the xanthophyll class and can be found mainly in Marigold flowers, egg products, leafy greens, and vegetables such as corn and potatoes. Lutein has been shown to be effective at retarding the development of age related macular degeneration, which is attributed to its ability to aid the activation of nuclear factor erythroid 2-related factor 2 target genes in human retinal pigment epithelial cells (Frede, Ebert, Kipp, Schwerdtle, & Baldermann, 2017). However, the major problem with lutein is its stability in-vivo which further leads to low bioavailability (Steiner, McClements, & Davidov-Pardo, 2018). Thermal degradation of lutein involves multiple steps that ultimately lead to a colorless product (Xiao et al., 2018). Acidic environments play a major role in lutein degradation by creating labile 3-hydroxy-3′,4′-didehydro-beta,gammacarotene and 3-hydroxy-2′,3′-didehydro-beta,e-carotene intermediates (Nidhi, Sharavana, Ramaprasad, & Vallikannan, 2015). Enzymatic degradation of lutein leads to formation of norisoprenoids (Mathieu, Bigey, Terrier, & Günata, 2007). Therefore, delivery systems with protective mechanism like solid-lipid nanoparticles, nanostructured lipid carriers and encapsulated formulations could help in prevention of labile biological components and, thus, improve overall efficiency of nutraceuticals. Details of some nutraceuticals with their pharmacological benefits and pharmaceutical limitations are listed in Table 1.

though, facilitates its permeability, yet rapid degradation at physiological conditions and extensive metabolism hamper its permeability (Grynkiewicz & Ślifirski, 2012). According to the BCS class, curcumin belongs principally to a class II or class IV agent (Wahlang, Pawar, & Bansal, 2011). Silymarin, a potential phytochemical compound obtained from the seeds of Silybum marianum plant has been used as a hepatoprotective agent for more than a decade. However, silymarin has poor oral bioavailability due to extensive phase II metabolism, low permeability across intestinal epithelial cells, low aqueous solubility, and rapid excretion in bile and urine (Ahmad et al., 2015). ‘Crocin’ is a natural carotenoid and is the bioactive principle of saffron (Crocus sativus L.) It protects human brain against oxidative stress and possesses antitumor and anticancer activities (Mousavi et al., 2011). Crocin has also been reported to have significant anti-proliferation effects on human colorectal cancer cells (Aung et al., 2007). It is water soluble carotenoid but has poor bioavailability profile. Studies showed that crocin is not absorbed throughout the gastrointestinal tract. After oral administration of crocins, it is priorly hydrolysed to crocetin or through intestinal absorption, the absorbed crocetin is partially metabolized to mono- and di-glucuronide conjugates (Asai, Nakano, Takahashi, & Nagao, 2005). Other bioactives like lycopene, rutin, quercetin, resveratrol etc. are unable to show their full therapeutic potential either due to stability issues in-vivo or have low aqueous solubility and low oral bioavailability. These agents could be successfully delieverd in-vivo by developing nanoformulations thereby minizing the limitations associated with them. Encapsulation technology may prevent the bioactive from photodegradation, thermal stability and g.i.t degradation. Lipid a major component of food, vitamins and minerals are susceptible to oxidation which can lead to its bad taste and degradation, but all of these could be encapsulated inside novel carrier systems to avoid these problems (Fathi, Mozafari, & Mohebbi, 2012). Release behavior in-vivo could be modulated by liposomes, solid lipid nanoparticles and other colloidal systems. More details and examples of such bioactives utilizing colloidal systems to overcome issues of solubility and bioavailability have been discussed further in the manuscript under different formulation categories. 2.2. Interaction with food and gastrointestinal constituents Our gastro-intestinal fluid contains enormous amount of constituent. There can be two sources of these constituents which are present in our gastro-intestinal fluid, (i) Enzymes, mucus, mineral, bile 5

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Fig. 2. Size of nanoparticulate systems used in nutraceuticals.

3. Nanotechnology based systems as a tool for delivery of nutraceuticals components

the nutraceutical formulation. A renowned Israel based nutraceutical company, NutraLease, is focused on enhancing the action of functional compounds. Their beverages and food products bearing encapsulated functional (active) compounds like omega-3, β-carotene, lutein, lycopene, coenzyme Q10, phytosterols, isoflavones, and vitamins A, D, and E are already available on the market (NutraLease, 2011a). All of these nutraceuticals have poor water solubility and low oral bioavailability. NutraLease’s technology is based on self-assembled nanoemulsions, which are used to enhance the encapsulation rate and bioavailability of functional compounds in the living body (NutraLease, 2011b). Encapsulation of bioactives prevents them from oxidation thereby improving the shelf life of nutraceutical. Another example where encapsulation is extensively employed is in delivery of Probiotics. It involves delivery of live bacterial cells to the gut of humans to exploit their multiple benefits. An example is Dr. Kim’s probiotic nanofood combination with calcium, which reduces the risk of osteoporosis (Wani et al., 2016). Despite the multiple functions exhibited by probiotic microorganisms, maintenance of the cell viability in probiotic-containing products is still a considerable challenge. First, during industrial processing, the microorganisms must undergo survival. Second, as these products are intended for oral use, the remaining viable cells undergo further stresses during the gastrointestinal passage due to changes in pH or contact with bile salts, which might disrupt the membrane of microorganisms. As a consequence, additional loss in cell viability is expected, before they even reach their target (Haffner, Diab, & Pasc, 2016). Encapsulation of probiobiotics may help in delivering viable bacteria to the gastrointestinal tract of the host (Shori, 2017). This methodology provides a protective coating to the probiotic bacteria and separates it from surrounding environment, and also appears to provide protection of cells from mild heat treatment. Song, Ibrahim, and Hayek (2012) showed better survival rate of alginate microencapsulated cells as compared to the free cells and were remarkably more effective in delivering viable cells to the colon than its non-encapsulated form. In this aspect, encapsulation of probiotic bacteria provides beneficial effects to enhance the viability as well as the survival rates of probiotic bacteria.

Absorption of nutraceuticals is hindered due to their limited aqueous solubility. Researchers are putting in their hard effort to fabricate dosage form of nutraceuticals that retains its identity of providing health benefits without compromising its intestinal absorption. Products which are based on nanotechnology can easily solve this purpose. Some of the methods which can be utilized in delivery of nutraceuticals is depicted in Fig. 2 with their size in nanometer. A delivery-system acts as a means for conveying any functional ingredient to the targeted site of action. It should perform several critical purposes for the functional ingredient beyond the basic addition by; (i) protecting it from degradation during processing, storage, and utilization, (ii) controlling its release rate and/or various environmental conditions like pH, ionic strength and temperature, and (iii) competing with other components in the system for achieving better appearance, texture, taste, and shelf-life. Delivery technologies, such as polymerbased nanoparticles, micelles and liposomes are under intensive study at present time. One common advantage of these nanosystems is the higher intracellular uptake than micro-sized particles (Orive, Hernandez, Gascón, Domínguez-Gi, & Pedraz, 2003). Details of drug delivery system which are employed for increasing the solubility and bioaccessibility of nutraceuticals are listed in Table 2. 3.1. Encapsulation of nutraceuticals components Over the last few years, various delivery systems have been explored by researchers and some of the established methods are now being utilized for effective delivery of dietary products. Nanoencapsulation is the process of enclosing one component within another material at the sizes on nanoscale by applying specific methods, thereby increasing the functionality of final product by controlled release of core. This technique protects vitamins, anti-oxidants, proteins, lipids, carbohydrates and aromas, which are mostly available as the active lipophilic substances in liquid form (Sekhon, 2010), as in the case of encapsulation of oil drops into a solid matrix (Turchiuli et al., 2005). Each delivery system has its own characteristics depending on ability of protection, costing, recognition as safe, ease of use, biodegradability, and biocompatibility (Acosta, 2000; Sekhon, 2010; Wood, 2005). The main objective of encapsulation is to provide stability and more robustness to

3.2. Formation of association colloids and micelles A colloid is a stable and heterogeneous system that consists of small insoluble particles, dispersed throughout another substance, whose 6

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∼200 nm 24 nm 119–152 nm 218 nm Diverse size 164–168 nm 53–106 nm ∼40 nm 79–94 nm 62–135 nm 128–235 nm ∼78 nm

Quercetin

Coenzyme Q10

Capsaicin Puerarin Fish oil

Lycopene

Resveratrol Silymarin

Lacatusu et al., 2013

To assess the biodistribution study of camptothecin loaded solid lipid nanoparticles after oral administration To improve ability to inhibit the chemical degradation of encapsulated lipophilic component To obtain a sustained plasma level To improve the oral bioavailability enhancement of resveratrol To explore the behaviour of fish oil enriched with ω-3 fatty acids in order to obtain stable lutein NLCs as effective delivery system To investigate the influence of surfactant composition on physical and oxidative stability of quillaja saponinstabilized lipid particles with encapsulated ω-3fish oil. To develop a novel and promising carrier system for the improved delivery of coenzyme Q-10

∼196 nm 168–227 nm Diverse size 134 nm

Coenzyme Q10 500–700 nm 66–92 nm 429 nm

85 nm

Fish oil

Curcumin Coenzyme Q10 Lutein

139–163 nm

Lutein

NLC

Nanocrystal

167–390 nm

Camptothecin β-carotene Melatonin Resveratrol

To enhance the solubility and bioavailability of curcumin To improve the oral bioavailability of coenzyme Q10 To improve adsorption and dermal penetration of lutein

Yang, Zhu, Lu, Liang, & Yang, 1999 Qian et al., 2013 Kandimalla, Babu, & Singh, 2010 Pandita et al., 2014

To explore the potential of a liposomal delivery system to modulate the bioaccessibility of carotenoid To improve the oral bioavailability of melatonin To improved stability and obtain a sustained release formulation

Diverse size Diverse size Diverse size 70–100 nm

Grape seed extract (Procyanidine) Carotenoids Melatonin Resveratrol

Vitamin E acetate

(continued on next page)

Rachmawati et al., 2013 Zhou et al., 2014 Mitri, Shegokar, Gohla, Anselmi, & Müller, 2011

Salminen, Aulbach, Leuenberger, Tedeschi, & Weiss, 2014 Keck et al., 2014

Tan et al., 2014 Keller, 2001 Amri, Chaumeil, Sfar, & Charrueau, 2012

Keller, 2001

Lee & Tsai, 2010 Gokce et al., 2012 Padamwar & Pokharkar, 2006

200 nm 300 nm Diverse size

Coenzyme Q10

Quercitin

Huang et al., 2011 Takahashi et al., 2009 Shin et al., 2013 Frenzel et al., 2015

To improve the oral bioavailability and brain distribution of (+)-catechin To enhance bioavailability and antioxidant properties of liposomal curcumin To improve liposome stability, mucoadhesive properties and oral adsorption To evaluate effect of weigh protein isolate coated and spray-dried liposomes as a carrier to enhance stability and permeability Improved skin permeation A comparative study between liposomes and solid lipid nanoparticles was done to see antioxidant effect. Study shows improved encapsulation efficiency and deposition of vitamin E in form of liposomes as compared to normal cream To improve solubility, faster onset of action and enhanced bioavailability

Sessa et al., 2014 Parveen et al., 2011

Choi et al., 2013 Yu et al., 2011 kumar Dey, Ghosh, Ghosh, Koley, & Dhar, 2012 Kim, Ha, Choi, & Ko, 2014

Belhaj et al., 2012

Hatanaka et al., 2010 Liang, Shoemaker, Yang, Zhong, & Huang, 2013 Salvia-Trujillo, Qian, Martín-Belloso, & McClements, 2013 Qian, Decker, Xiao, & McClements, 2012 Gui et al., 2008 Pinheiro et al., 2013 Yu & Huang, 2012 Karadag, Yang, Ozcelik, & Huang, 2013

Gonnet, Lethuaut, & Boury, 2010 Li, Zheng, Xiao, & McClements, 2012

Reference

35–70 nm 263 nm 101–203 nm Diverse size

Optimization of homogenization evaporation process for lycopene nanoemulsion production and its beverage applications To enhance the oral bioavailability of encapsulated resveratrol To improve solubility and bioavailability of silymarin

To study the influence of carrier lipid concentration and type (MCT and LCT) on triglyceride digestibility and β-carotene bioaccessibility To obtain β-carotene nanoemulsions with better stability and higher bioaccessibility To enhance the oral bioavailability of berberine To protect the degradation and assess release of lipophilic curcumin Formation of organogel based nanoemulsion to improve bioavailability of curcumin To prepare quercetin loaded nanoemulsions with nonionic food-grade emulsifiers to provide stability to curcumin To evaluate the pharmacokinetic properties of CoQ10 using three orally administered formulations (salmon oil, salmon lecithin, soybean oil) To examine the pharmacokinetic properties of the formulated capsaicin nanoemulsions To improve bioavailability of puerarin after nasal administration of nanoemulsion To improve the intestinal absorption of fish oil by nanoemulsion formation

To enhance the absorption of liposoluble vitamins in form of nanoemulsion To improve the delivery of 5-Hydroxy-6,7,8,4-tetramethoxyflavone (Gardenin B) by nanoemulsion as a carrier system To enhance the oral bioavailability and pharmacological effects of α-tocopherol To improve stability of O/W nanoemulsion by using modified starch

Purpose of study

(+)- Catechin Curcumin

Berberine Curcumin

SLN

Liposomes

80–400 nm 142–250 nm

α-tocopherol β-carotene 146–415 nm

30–60 nm ∼150 nm

Vitamin A,D,E,K Gardenin B

Nanoemulsion and microemulsion

Size range

Active food component

Nano carrier system

Table 2 Novel carrier systems for enhanced delivery of nutraceuticals.

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Tan, Liu, Chang, Lim, & Chiu, 2012 Kim, Seo, & Lim, 2013

Semo, Kesselman, Danino, & Livney, 2007

15–18 nm 16–30 nm Quercetin β-carotene

To formulate nanoparticles to evaluate encapsulation and protective effect of the micelles against photochemical degradation of vitamin To improve solubility and stability of quercitin To improve stability against oxidation and enzymatic digestion 147–156 nm

80–600 nm Lutein

Vitamin D2

72–119 nm Coenzyme Q10

sizes range within 1 to 1000 nm in diameter. An association colloid is defined as an amphiphilic class of colloids, whose particles are made up of even smaller molecules such as bile salts, and fatty acids (Flanagan & Singh, 2006; Letchford & Burt, 2007; Patel & Velikov, 2011; Velikov & Pelan, 2008). Association colloid is a transparent and spontaneously dissociating system, and its size ranges in between 5 and 100 nm. Colloidal delivery systems can be classified into three major attributes in terms of composition, size, morphology and surface and these are: (i) Dispersions of solid-in-liquid, (ii) Dispersion of liquid-in-liquid, and (iii) Dispersion of self-assembled molecules. The key challenge is to prepare a cheaper and much more effective colloidal particle based on foodgrade proteins (Dickinson, 2010). Functional ingredient can be incorporated into a product by two simple methods: (i) Soluble form can be incorporated as a solution, and (ii) Insoluble form can be incorporated as a dispersion. Among them, adding an ingredient in the soluble form is more advantageous if solubility permits it. Hence, the availability of the soluble component for absorption increases its bioaccessibility and taste characteristics with an increased chemical reactivity (Patel & Velikov, 2011). A micelle is a type of colloidal system of amphiphilic molecule. A micellar system is an effective delivery system having small size less than 10 nm, and is thermodynamically stable (Boyd, 2008; Naksuriya, Okonogi, Schiffelers, & Hennink, 2014). Advantages of polymeric micelles include (i) drug loading capacity is high, (ii) remarkable improvement in water solubility, (iii) decrease in toxicity and adequate small size (so that it can circulate in the systemic circulation for a longer period of time). For example casein micelles were used to solubilize curcumin which is a phenolic compound obtained from turmeric, a member of family Zingiberaceae. It is a potent antioxidant and anti-inflammatory molecule. The phenolic hydroxyl group is responsible for its antioxidant activity. Additionally, it has ferric ion reducing potential as well as ferrous ions chelating action. Besides the numerous activities, curcumin suffers from various drawbacks such as low stability, permeability, and bioavailability (Rauf, Imran, Orhan, & Bawazeer, 2018). Casein micelles resulted in increased stability and solubility of curcumin in the relevant physiological condition (Sahu, Kasoju, & Bora, 2008), and to increase the cellular uptake of curcumin, the carotenoid in the phospholipid micelles helped, while anthocyanins in apolar medium helped by reverse micellization process (Kim et al., 2003). Thin film hydration method was used to fabricate mixed micelles which are Curcumin loaded to investigate physicochemical properties and release behavior of curcumin in-vitro (Zhao et al., 2012). Results showed that release pattern was sustained for curcumin and an encapsulation efficiency of 87% was achieved. Increased bioactivity and enhanced solubility of curcumin were the result of investigation which suggests that mixed micelles may act a nano-carrier system with great potentials (Zhao et al., 2012). The impact of phytic acid on lipid digestion and curcumin bioaccessibility in oil-in-water nanoemulsions was investigated by Pei et al. (2019). The authors measured the level of free fatty acids (FFAs) generated and the bioaccessibility of curcumin after the small intestine stage. An inverse relationship between lipolysis and curcumin bioaccessibility was ascribed to the impact of phytic acid on droplet flocculation and the level of free calcium ions present, which affected the production of mixed micelles capable of solubilizing the nutraceutical (Pei et al., 2019). Recently Piazzini et al. (2019) developed two novel nanomicellar formulations to improve the poor aqueous solubility and the oral absorption of silymarin, a widely used herbal hepatoprotective agent. Polymeric nanomicelles made of Soluplus and mixed nanomicelles combining Soluplus with d-α-tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS) were prepared using the thin film method. Evaluations reveal formation of nanomicelles in sizes of ~60 nm having narrow size distribution (polydispersity index ≤0.1) and encapsulation efficiency > 92% indicated the high affinity between silymarin and the core of the nanomicelles. Solubility studies demonstrated that the solubility of silymarin increased by ~6-fold when loaded into nanomicelles (Piazzini et al., 2019). These studies

Micelles

Arunkumar et al., 2013

Swarnakar et al., 2011

Yen et al., 2009 Yen, Wu, Lin, Cham, & Lin, 2008

To improve the physicochemical properties and hepatoprotective effects of naringenin nanoparticles To prepare nanoparticles of cascuta chinensis to evaluate efficacy of acetaminophen induced hepatotoxicity in rats To evaluate crystallinity of drug, stability in simulated GI fluids and accelerated storage stability and to test cellular uptake, sub cellular localization and antioxidant activity as well as hepatoprotective efficacy and anti-inflammatory activity of CoQ10-NPs To develop water-soluble low molecular weight chitosan (LMWC) nanoencapsules of lutein and improve its bioavailability 65 nm 267 nm Naringenin Cascuta chinensis Polymeric nanoparticles

Table 2 (continued)

Size range Active food component Nano carrier system

Purpose of study

Reference

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core emerged to be a suitable carrier for water insoluble quercetin (Frenzel, Krolak, Wagner, & Steffen-Heins, 2015). Crocin’ is a natural water soluble carotenoid but has poor oral bioavailability. Few researchers have explored possibility of employing liposomal crocin as an anti-tumor and anticancer intervention. Mousavi et al. (2011) prepared liposomal crocin by dehydration and rehydration method and tested it against cancer cell lines. HeLa and MCF-7 were considered samples for malignant cells, and mouse fibroblast cell line (L929) as nonmalignant control cell in this study. Both malignant and nonmalignant cells were treated with free crocin (1, 2, and 4 mM) and liposomal crocin (0.5 and 1 mM crocin, with different lipid composition). Results reveal a decreased cell viability by crocin and liposomal crocin in malignant cells but not in nonmalignant cells (Mousavi et al., 2011). Their observation proved that the liposomal formulations containing crocin had better cytotoxic effects and could reach inner cancer cells more effectively compared with the free crocin. Scrutiny of cell cycle revealed that both free crocin and liposomal crocin induced a subG1 peak which is a biochemical marker of apoptosis; corroborating the anticancer potency of liposomal crocin (Mousavi et al., 2011). Similar investigations have been done on lycopene, β-carotene, lutein and canthaxanthin and results show a fast release pattern for lycopene and canthaxanthin whereas lutien and beta carotene demonstrated controlled and sustained relaease profile (Steiner et al., 2018; Tan et al., 2014). These studies indicate liposomes to be a good choice for delivery and bioavailability enhancement of both lipophilic (curcumin, quercetin) and hydrophilic (crocin) bioactives.

suggest that formation of micelles assists in solubilization of nutraceuticals in-vivo. 3.3. Liposomes Nanoscale lipid vesicles are referred to as nanoliposomes or merely nanometric adaptations of liposomes. The indispensable hydrophilic–hydrophobic interface, linking phospholipids and water molecules, is responsible for the formation of nanoliposomes (Aadinath, Bhushani, & Anandharamakrishnan, 2016). These are minute spherical sac of unilamellar or multilamellar phospholipid bilayer molecules enclosing a water droplet, especially formed artificially to carry drug or other substances into the cell (Brandl, 2001; Musthaba, Baboota, Ahmed, Ahuja, & Ali, 2009). Stealth liposomes are made up of polyethylene glycols (PEG) which helps them to avoid phagocytic uptake and circulate for longer duration (Gregoriadis, 2006). The size of liposomes varies for different biological applications and is ususally in the range of 50–1000 nm (Daraee, Etemadi, Kouhi, Alimirzalu, & Akbarzadeh, 2016). The various fabrication methods include sonication, extrusion, microfluidization, and heating methods (Xia et al., 2014). Evaluation is decisive to ensure quality of product while using new techniques. The most significant consideration of their characterization embraces visual manifestation, size distribution, stability, zeta potential, lamellarity, and entrapment efficiency (Gülseren & Corredig, 2013; Shin, Chung, Kim, Joung, & Park, 2013). The in-vivo behavior of liposomes can be affected by composition of lipid from which it is made, the charge on it and the size of the vescicles (Taylor, Weiss, Davidson, & Bruce, 2005). Liposomes acts by two ways, (i) specific drug delivery through macrophage, (ii) targeting of drug in a passive manner, which ensure active constituent to be released slowly over a period of time and get into systemic circulation from the liposomes. However, high costs of organic solvents and/or synthetic surfactants in their preparation process are the major limitations to their effective utilization in the food sector. Curcumin has potent aniti-inflammatory activities and is widely used as a food additive, but it is unable to show its effect in-vivo due to its low aqueous solubility and bioavailability. Recent studies on the use of liposomes in certain foods has focused on binding of phosphatidyl choline with curcumin to fabricate curcumin as a material which serves as a functional food (Musthaba et al., 2009). To increase its gastrointestinal absorption researchers prepared liposome encapsulated curcumin and observed that the plasma antioxidant activity of oral liposomal curcumin was enhanced as compared to other treatments (Takahashi, Uechi, Takara, Asikin, & Wada, 2009). In another work on curcumin liposome a comparison was done by varying the methods of preparation to study its effect on encapsulation efficiency. It was observed that liposomes prepared by ethanol injection method had better encapsulation efficiency compared to dry thin film method. This formulation enhanced bioavailability, with enhanced high mucoadhesive property, storage stability, and encapsulation efficiency (Shin et al., 2013). Recent developments on curcumin liposomal preparation comprises of encapsulating the vesicles in cyclodextrins to obtain sustained drug release. Encapsulation of curcumin (Cur) in “drug-in-cyclodextrinin-liposomes (DCL)” by following the double-loading technique (DL) was done and results reveal that drug release profiles showed a sustained release after an initial burst effect, fitting to the KorsmeyerPeppas kinetic model. Moreover, a direct correlation between the area under the curve (AUC) of dissolution profiles and flexibility of liposomes was obtained (Fernández-Romero, Maestrelli, Mura, Rabasco, & González-Rodríguez, 2018). Quercetin is a phytoconstituent having dynamic pharmacological properties, but just like curcumin it has stability problems in gastrointestinal tract. To overcome this, investigators prepared quercetin loaded liposomes and coated it using whey protein isolate. From the results it was observed that the stability of quercetin in-vivo was greatly enhanced, the bitter taste was masked due to coating and liposomal

3.4. Nanoemulsion and microemulsion Nanoemulsion comprises of words nano and emulsion. It refers to an emulsion having particles in the nanometer range (10-9 m) (Ali, Ansari, Ahmad, Akhtar, & Jahan, 2017). Nanoemulsion may be defined as mostly transparent or sometimes milky dispersion of oil and water stabilized by surfactant molecule which serve as an interfacial film between the two immiscible liquids. Nanoemulsion are thermodynamically and/or thermokinetically stable system (Qadir, Faiyazuddin, Hussain, Alshammari, & Shakeel, 2016). Size range of nanoemulsion range between 10 and 100 nm (Shafiq et al., 2007). Nanoemulsions could be prepared by both high energy methods and low energy methods. High energy involves use of high pressure homogenizers, microfluidizer and probe sonicators. Low energy method includes self emulsifying systems, phase inversion system, aqueous titration methods etc. (Ali et al., 2017). Difference between these two systems is that microemulsions are spontaneously formed where as nanoemulsion relatively are more time consuming during development, the amount of surfactant used in nanoemulsion is far less than that used in microemuslion (Shakeel, Shafiq, Haq, Alanazi, & Alsarra, 2012). Advantages of nanoemulsion includes ease of formation, stability, clarity, increased absorption rate leading to increasing in bioavailability and potential to form a formulation with both lipophilic as well as the hydrophilic drug. Long lasting stability (up to years) and ability to encapsulate both lipophilic and hydrophilic drug has given this colloidal system a valuable position in drug delivery (Ali et al., 2017). The dispersed-droplet-diameter, 500 nm or less, of an emulsion makes it one of the commonest of colloids for food applications (McClements & Rao, 2011). The functional ingredients are encapsulated in nanoemulsions within their droplets, leading to reduced chemical degradation (McClements & Decker, 2000). Increased utilization of nanoemulsion in the food industries for certain applications has been widely found because of its unique physico-chemical properties of high bioavailability, physical stability, encapsulation efficiency, lowered turbidity and bioavailability (Dickinson, 2012; Qian & McClements, 2011; Rozner et al., 2010). Investigators prepared oil in water nanoemulsion of eicosapentanoic acid and decosahexanoic acid rich fish oils to enhance their absorption rate in-vivo. High speed homogenization and ultrasonication methods were used for preparation of 9

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Attractive features, such as increased dissolution velocity, increased saturation solubility, improved bioadhesivity, versatility in surface modification and ease of post-production processing, could be employed to minimize the problems associated with nutraceuticals.

nanoemulsion and droplet size of 79–94 nm was achieved. It was observed that absorption rate at this droplet size was significantly enhanced (Kumar, Ghosh, Ghosh, Koley, & Dhar, 2012). Resveratol has low solubility in aqueous environment and it is sensitive to biological as well as chemical degradation. To overcome this, an attempt was made by researchers to encapsulate Resveratol in oil based nanoemulsion system to enhance bioavailability, stability and chemical permeation through intestinal cell wall (Sessa et al., 2014; Sessa, Tsao, Liu, Ferrari, & Donsì, 2011). Bioavailability of silymarin, a potent hepatoprotective agent was enhanced many folds when delivered in form of nanoemulsion (Ahmad et al., 2017). These studies suggest that advantages of nanoemulsion like easier methods of fabrication and fast oral absorption could be harnessed to deliver and enhance bioavailability of wide range of nutraceuticals.

3.6. Delivery of nutraceuticals in form of nanoparticles (solid-lipid, polymeric and nanostructured lipid carriers) Nanoparticle are core shell particles with one dimension having at least the size of less than 100 nm. Nanoparticles are broadly categorized into two different formulations based on their composition i.e. polymeric nanoparticles and lipid nanoparticles. The latter is further categorized as solid-lipid nanoparticles (SLN), and nanostructured lipid carriers (NLC). A polymeric colloidal nanoparticle made up of a polymer such as chitosan, gelatin, albumin, polylactideco-glycolide and poly lactide, and a pure compound (Soppimath, Aminabhavi, Kulkarni, & Rudzinski, 2001; Wood, 2005). When a bioactive compound is embedded using a carrier material ususally lipids that are solid at room temperature it is referred to as solid lipid nanparticle. Aqueous dispersions of SLN contain between 0.1% and 30% w/w of solid lipids and are stabilized by a surfactant whose concentration varies between 0.5% and 5% w/w (Joshi & Müller, 2009; Pardeike, Hommoss, & Müller, 2009). However, solidification and subsequent crystallization of the lipid from the dispersed phase in the SLN lead to the expulsion of the active substances, which constitutes a serious problem of instability (Westesen, Bunjes, & Koch, 1997). This leads to an increase in particle size and a decrease in the load capacity (Pardeike et al., 2009; Weber, Zimmer, & Pardeike, 2014). To overcome the stability issue, a new colloidal system was developed from binary mixtures of lipids in which part of the solid lipid is replaced by a liquid lipid or a mixture of liquid lipids (Jenning, Thünemann, & Gohla, 2000), giving rise to the Nanostructured Lipid Carriers (NLC). The advantages of the NLC over the SLN include a better loading capacity of the active molecule because a good quantity of it can be lodged in the imperfections of the particle avoiding the early expulsion of the active ingredient (Joshi & Müller, 2009). NLC offer greater stability and prevent recrystallization of solid lipids and, thus, the size remains practically unchanged during storage (Pardeike et al., 2009;16). Nanoparticles provide broader applications for nutraceuticals owing to the following; (i) lesser dose of bioactive compound is needed (ii) superior bioavailability of active compound is obtained, (iii) nanoparticles are mechanically and thermally more stable to changing pH, (iv) Nanoparticles show better shelf-life, (v) matrix selection helps in formulating controlled release preparation, (vi) attaching ligands to the surface of particle, site-specific targeting can be achieved (vii) the formulation can be employed for oral, nasal, parenteral, intra-ocular administrations etc. (Han, Xu, Taratula, & Farsad, 2019; Luo, Zhang, Cheng, & Wang, 2010; Vozza, Khalid, Byrne, Ryan, & Frias, 2019). Nanoparticles have provided the development of novel foods by incorporating vitamins, probiotics, bioactive peptides and antioxidants into the food matrix that may have certain positive physiological benefits (De Britto, de Moura, Aouada, Mattoso, & Assis, 2012). The incorporation of nanoparticles with novel functional foods has provided enhancement of bioavailability and color changes in the compounds containing zinc and iron, proteins to form gels for encapsulation of bioactive compounds, vitamins for development of new carriers and active systems with a better biocompatibility and biodegradability (Chen, Remondetto, & Subirade, 2006; Matalanis, Jones, & McClements, 2011; Sekhon, 2010).

3.5. Nanosuspension (Nanocrystal) One of the ways to get rid of the stability issue of suspension is to reduce its particle size. Nanocrystal suspensions or nanosuspension contains only crystals of pure bioactive compound and are carrier free nanoparticles in nature and for its stabilization purpose only minimum amount of surfactant and/or polymer is used (Rabinow, 2004). Nanosuspensions can be defined as colloidal dispersions of nano-sized drug particles that are produced by a suitable method and stabilized by a suitable stabilizer. They can be manufactured by using high pressure homogenizers (Disso Cubes) or by media milling technique (Patravale & Kulkarni, 2004). Advantages associated with nanosuspension are: (i) drug can be loaded in high amount, (ii) stability of core compound in solid state is increased (iii) solubility rate is high (iv) bioactive components having poor solubility show increased dissolution rate when deliverd in form of nanosuspension (Patravale & Kulkarni, 2004). Due to these reasons they have been used as a tool for delivery of food components. α-tocopherol is a liposoluble vitamin and is so commonly used as an antioxidant and as a supplement in food, cosmetic and pharmaceutical sciences. However it has low aqueous solubility and availability in the systemic circulation. Supercritical Assisted Injection in a Liquid Antisolvent (SAILA) technology has been employed by researchers to enhance solubility, dissolution rate and bioavailability of prepared α-tocopherol nanosuspension (Campardelli & Reverchon, 2015). Quercitin was formulated as nanosuspension by High Pressure Homogenization (HPH) technique using Tween 80 as a surfactant and Maltdextrin as encapsulating agent. The resulting formulation was further spray dried. Quercitin nanosuspension showed enhanced solubility and bioavailability (Karadag, Ozcelik, & Huang, 2014). Aditya, Yang, Kim, and Ko (2015) fabricated nanosuspension of curcumin using β-lactoglobulin to enhance solubility, stability, and bioavailability. The aim of this work was to reduce the size of curcumin crystals to the nanoscale and subsequently stabilize them in an amorphous form. To this end, amorphous curcumin nanosuspensions were fabricated using the antisolvent precipitation method with β-lactoglobulin (β-lg) as a stabilizer. The resulting amorphous curcumin nanosuspensions were in the size range of 150–175 nm with unimodal size distribution. The solubility of the amorphous curcumin nanosuspension was enhanced ~35-fold due to the reduced size and lower crystallinity. Amorphous curcumin nanosuspensions stabilized with β-lg and prepared at pH 3.4 (β-lg-cur 3.4), showed maximum aqueous stability which was > 90% after 30 days. An in-vitro study using Caco-2 cell lines showed a significant increase in curcumin bioavailability after stabilization with βlactoglobulin (Aditya et al., 2015). Similarly, curcumin nanosuspension were developed by High Pressure Homogenization technique to enhance its stability in-vivo (Rachmawati, Shaal, Müller, & Keck, 2013). Nanosuspensions are unique and yet commercially viable approach to combating problems such as poor bioavailability that are associated with the delivery of hydrophobic drugs. Production techniques such as media milling and high-pressure homogenization have been successfully employed for large-scale production of nanosuspensions.

3.6.1. Solid-lipid nanoparticles (SLNs) Solid lipid nanoparticles are also colloidal carriers similar to nanoemulsion but with few alterations in composition. The liquid lipid or oil phase of nanoemulsion is replaced by lipids which are solid at room temperature like paraffins, triacylglycerols etc (Pardeshi et al., 2012). SLNs usually have mean diameters in the range of 50–1000 nm, consisting of solid lipidic cores, inside which active compounds can be 10

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pharmacological benefits. However, problems like thermal, chemical and enzymatic degradation pose serious stability issues in-vivo which further leads to low bioavailability (Mathieu et al., 2007; Nidhi et al., 2015; Steiner et al., 2018; Xiao et al., 2018). These problems could be minimized by utilizing the merits of NLCs which is by far the most preferred delivery system while addressing stability issues of bioactives. Nutraceuticals could be loaded inside the lipid phase for protection against thermal, chemical and enzymatic degradations. Apart from imparting stability and robustness to the formulation NLCs could modulate the release behavior of bioactives thereby affecting their availability in systemic circulation. Lutein has shown to exhibit slow release mechanism in-vivo in NLC form (Lacatusu et al., 2013). Curcumin loaded NLC were prepared for intra-gastric administration and results indicate that bioavailability was enhanced and curcumin was detected in spleen, kidney, heart, liver, lungs and brain during tissue distribution studies (Fang et al., 2011). Similar research was done on quercitin and it was observed that in NLC form quercitin shows slow release pattern and enhanced bioavailability (Liu et al., 2014). Zhang et al. successfully encapsulated β-carotene in NLC for use in food and beverage system (Zhang, Hayes, Chen, & Zhong, 2013). All these studies on bioactives suggest that the advantages of NLCs could be harnessed for enhancing the in-vivo stability of nutraceuticals.

dispersed, and are coated with a phospholipid monolayer on the outside (Emeje, Obidike, Akpabio, & Ofoefule, 2012). Some of the advatanges of SLNs are; (i) It is small in size hence surface area is large for better absorption of nanoparticles thereby increasing bioavailability and eventually increased therapeutic effect (ii) Increased drug loading capacity, (iii) better interaction at the interface (where two phase meet each other) (Ghasemiyeh & MohammadiSamani, 2018). These mentioned advantages are attracting investigators from across field to enhance the activity of pharmaceutical and nutraceuticals (Cavalli, Caputo, & Gasco, 1993; Fathi et al., 2012; Muller & Runge, 1998). Many techniques are available for preparation of solid-lipid nanoparticles but depending on whether heat is utilized or not they are further divided into two types namely, Hot Homogenization and Cold Homogenization methods. SLNs for heat stable nutraceuticals can be prepared via hot homogenization technique whereas thermolabile constituents have to be manufactured using cold homogenization method (Pardeshi et al., 2012). In recent years lot of research on curcumin has been done to enhance its solubility and bioavailability. Investigators prepared SLNs for curcumin by hot homogenization technique using Dynasan® 114® and Sefsol-218® as the lipid phase. Evaluation results reveal that 90% of curcumin was encapsulated inside the lipid core having particle size of 152.8 ± 4.7 nm. It was also observed that curcumin SLN showed improved pharmacokinetic properties in rats and the bioavailability increased by 1.25-folds leading to prolonged inhibition of MCF-7 cancer cell lines (Sun et al., 2013). Resveratrol is a phytoalexin found naturally in many biological sources such as grapes, berries, legumes, and flowers. It is one of the most studied stilbenes. It acts a cancer chemopreventive agent, a cardioprotective agent, and shows antioxidant, antiinflammatory, neuroprotective, and antiviral properties. Resveratrol triggers apoptosis, promotes cell cycle blocking, and influences signal cascades linked to kinase pathways, without evidence of toxicity when studied in animal models (Tellone, Galtieri, Russo, Barreca, & Ficarra, 2019). However just like curcumin, resveratrol also has poor aqueous soulibility and bioavailability. To overcome this issue Pandita, Kumar, Poonia, and Lather (2014) prepared resveratrol SLN by solvent diffusion–solvent evaporation method utilizing stearic acid coated with poloxamer as the lipid phase. Evaluation results reveal that 88.9 ± 3.1% of resveratrol was encapsulated having men particle diameter of 134 ± 7.6 nm. The main objective of the study was to obtain a sustained release formulation with enhanced bioavailability. The investigators were successful in their objective as the lipid formulation showed prolonged drug release in vitro up to ~120 h and followed Higuchi kinetics and also exhibited a significant 8.035 fold improvement in the oral bioavailability of resveratrol as compared to drug suspension (Pandita et al., 2014). Similar study was also carried on β-carotene to enhance its stability and bioavailability (Oliveira, de Figueiredo Furtado, & Cunha, 2019; Qian, Decker, Xiao, & McClements, 2013). For over a decade SLNs have proved to be a good choice for delivery of bioactives in-vivo for solubility and bioavailability enhancement. Its ease of fabrication and higher loading capacity allows researchers to exploit it in wide range of nutraceuticals. The only limitation associated with SLNs is its instability on long term storage conditions, however they may be of preference for other reasons.

3.6.3. Polymeric nanoparticles (PNPs) PNPs are another coherent delivery system for insoluble hydrophobic agents having the particles size within the range of 1–100 nm (Mehanny, Hathout, Geneidi, & Mansour, 2016). These nanoparticles have the ability to protect therapeutic agents from degradation, and modifying their pharmacokinetic parameters such as absorption, metabolism, clearance, and elimination, to achieve the drug controlled release patterns (Mehanny et al., 2016). The most common polymers used to encapsulate therapeutic agents are poly D, L-lactic-coglycolide (PLGA), starch, hydroxypropyl methycellulose (HPMC), chitosan, dextran, and pectin (Emeje et al., 2012; Mehanny et al., 2016). These polymers are highly acknowledged for their safety profile, biocompatibility, biodegradability, and cost effectiveness (Emeje et al., 2012; Li et al., 2016; Mehanny et al., 2016). Drugs can be conjugated to the polymers or dispersed within the polymer matrix and are released by diffusion or due to controlled erosion of the particle (Parveen & Sahoo, 2008). Encapsulating drugs into polymeric nanoparticles protects them from degradation, enables sustained release, enhances intracellular penetration and improves bioavailability (Sanna, Siddiqui, Sechi, & Mukhtar, 2013). Polymeric nanoparticles minimizes the limitations posed by lipid based delivery systems. Bioactive compounds in polymeric nanoparticle can be released in a controlled manner which increases stability and high capacity for loading of drugs (Kamaly, Xiao, Valencia, Radovic-Moreno, & Farokhzad, 2012). Researchers have prepared curcumin nanoparticles using PLGA (Poly lactic-co-glycolic acid) as polymer by solvent evaporation method (Xie et al., 2011). Solubility of nanosized curcumin was 640-folds higher than pure curcumin and absolute bioavailability increased from 4.73% to 26.5%. This study provided evidence that PNPs are much better in enhancing the solubility of curcumin as compared to other delivery systems. Singh and Pai (2014) encapsulated resveratrol in PLGA nanoparticles to examine the effect on its release profile and bioavailability in-vivo. They fabricated different nanoparticles by varying the quantity of PLGA and emulsifier. Evaluation results indicated that the fabricated nanoparticles ranged in diameter between 90 nm and 365 nm, had a zeta potential between −24.7 mV and −27.6 mV and encapsulation efficiencies between 42% and 72%. Resveratrol was released over 12 days and the nanoparticles remained stable for at least 6 months. Their results revealed that encapsulation of resveratrol into PLGA nanoparticles increased the absorption rate constant 7-fold and the area under the curve 10-fold compared with both pure drug and a marketed resveratrol product, indicating a significant enhancement in bioavailability (Singh & Pai, 2014). Lutein PNPs were prepared using chitosan as a polymer

3.6.2. Nanostructured lipid carriers (NLCs) Lipid nanoparticles which employs liquid lipids in formulation are refereed to as Nanostructured Lipid Carriers. NLCs are much better in terms of stability then SLNs. NLCs tend to minimize the drawbacks associated with SLNs like low loading of drug, immediate release and stability related issues. NLCs show certain advantages like slow release profile of functional component and also provide protection from degradation. These advantages of NLCs have been applied in nutraceuticals for enhancing the bioavailability of functional food components. Lutein is part of the xanthophyll class which has numerous potential 11

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Table 3 Commercially available nutraceuticals in market utilizing nanotechnology. Product

Active component

Description

Manufacturer

Nanotea

Contains high content of selenium. Antioxidant

Effective release of constituent, thus boosting the adsorption (adsorbing viruses, free radicals, cholesterol and blood fat) and annihilation of viruses through penetration so that a good supplement of selenium could be achieved and its function can be increased by 10 times.

Qinhuangdao Taiji Ring Nano Products Company Ltd.

Canola Active Oil

Canola derived phytosterols

Utilizes proprietary manufacturing process NSSL (Nano Sized Self Assembled Structured Liquids) to prepare nanosized lipid micelles known as ‘Nanodrops’. Lipid micelles have improved solubility and absorption in the g.i.t and are designed to carry beneficial canola derived phytosterols. Nanodrops are competitively taken up by large bile derived micelles that normally carry cholesterol, thus inhibiting uptake and transportation of cholesterol.

Shemen Industries, Israel

OilFresh®

Oil conditioning device

It is an innovative catalytic device for longer and better oil usage. It is designed to interact with oil at the nano level to prevent its deterioration and its freshness. OilFresh® enhances oils heat conductivity for faster cooking at lower temperatures.

OilFresh Corporation, USA

Nanoceuticals™ Artichoke Nanoclusters

Artichoke

Nourishes immune system by scavenging free radicals Increase hydration Balance body pH Reduce Lactic Acid during exercise Reduce surface tension of supplements and foods to increase wetness and absorption of nutrients

RBC Lifesciences®

Novasol® ADEK-Q10

Vitamin A,D,E,K Coenzyme Q10

Prepared nanomicelles are stable with respect to pH and temperature and has a diameter of approximately 30 nm.

Aquanova®

LifePak®

Contains pack of vitamins, minerals, fatty acids and other ingredients

LifePak® Dietary supplement is indicated for Anti-ageing effect. Product also contains Nano form of coenzyme Q10 (ubiquinone). This proprietary formula protects DNA and cells, nourishes and protects the brain, bolsters the immune system, supports cardiovascular health, helps regulate blood sugar metabolism, protects eye health, helps build strong bones, promotes joint function and mobility, helps protect against the effects of sun radiation, and helps maintain healthy skin tone and elasticity.

Pharmanex®

NanoCoQ10®

Coenzyme Q10

Coenzyme in nano form provides much more bioavailability than in conventional form. Product is indicated for anti-ageing effects.

Pharmanex®

ACZnano® Advanced Cellular Zeolite

Zeolite

ACZ nano Extra Strength employs nano size and a significantly greater number of zeolite crystals per dose than other zeolite products, providing far greater surface area and superior results. It supports a healthy immune system, helps remove heavy metals, toxins and other substances from the body and helps balance pH levels in the body.

Vitality Products Co., Inc. USA

Nano Curcumin

Curcumin

Nano curcumin has been shown to generate much more activity than non-nano preparations of curcumin. It acts as powerful antioxidant, antiinflammatory, anti-viral and anti-cancer properties (especially for pancreatic and colo-rectal tumours).

Neurvana®

Nano Resveratrol

Resveratrol

Nanospheres of Resveratrol has better bioavailability and crosses the blood brain barrier and protects and enhances nerve function, improving memory and brain function. As an antioxidant it is a powerful inhibitor of inflammation and can help prevent cancer.

Neurvana®

Nano C

Vitamin C α-Lipoic acid Quercitin

Product in nano form ensures rapid absorption across the mouth mucosa and extended life and action in the body including passing across the blood brain barrier. This allows high doses to be taken without the usual side effects of other oral Vitamin C preparations. Product enhances the bioavailability of α-Lipoic acid and Quercitin in nano form.

Neurvana®

which has seven 7-membered sugar units linked by α-(1,4)-glycosidic bonds, is the most often used, as it is able to host guest molecules with molecular weights up to 800 g/mol (Gomes, Petito, Costa, Falcão, & de Lima Araújo, 2014; Szente & Szejtli, 2004). Inclusion complex of curcumin and β-CD was prepared by co-precipitation technique followed by freeze drying and evaporation of solvent. It was observe that encapsulation efficiency was 74%. The formulation yielded 18% more photo stability, 31 folds enhanced solubility, 99% color retention and stability over wide range of pH thereby enhancing overall efficiency of curcumin (Mangolim et al., 2014). In the nano sized form curcumin and β-CD complex exhibited better dissolution profile and enhanced permeability through skin (Rachmawati et al., 2013). Cyclodextrins are nontoxic; therefore, they have been exploited for various pharmaceutical applications, including being used as complexing agents to

and it was observed that solubility and bioavailability of prepared nanoparticles was significantly enhanced as compared to conventional formulations (Arunkumar, Prashanth, & Baskaran, 2013). In another study Vitamin A nanoparticles were prepared using chitosan as polymer for controlled release of tocopherol in animals (Quiñones et al., 2013). These studies indicated that bioactives in form of PNPs were more superior in performance as compared to parent compound. 3.7. Cyclodextrins (CD) complex Cyclodextrins belongs to acyclic oligosaccharide family, consisting of a hydrophilic outer part and an inner hydrophobic matrix. Therefore, CD can form inclusion complexes and/or host numerous hydrophobic compounds (Mangolim et al., 2014). Among all the CDs types; β-CD, 12

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increase the aqueous solubility of hydrophobic drugs; reducing their bitterness; and enhancing their bioavailability and stability (Szente & Szejtli, 2004; Tiwari, Tiwari, & Rai, 2010). At present a lot of nano sized nutraceuticals are commercially available in the market which have enhanced solubility and bioavailability. List of some developed nanonutraceuticals currently marketed are listed in Table 3.

degenerative diseases of aging. Proceedings of the National Academy of Sciences, 90(17), 7915–7922. Amri, A., Chaumeil, J. C., Sfar, S., & Charrueau, C. (2012). Administration of resveratrol: What formulation solutions to bioavailability limitations? Journal of Controlled Release, 158(2), 182–193. Arunkumar, R., Prashanth, K. V. H., & Baskaran, V. (2013). Promising interaction between nanoencapsulated lutein with low molecular weight chitosan: Characterization and bioavailability of lutein in vitro and in vivo. Food Chemistry, 141(1), 327–337. Asai, A., Nakano, T., Takahashi, M., & Nagao, A. (2005). Orally administered crocetin and crocins are absorbed into blood plasma as crocetin and its glucuronide conjugates in mice. Journal of Agricultural and Food Chemistry, 53(18), 7302–7306. Augustin, M. A., Sanguansri, L., & Lockett, T. (2013). Nano-and micro-encapsulated systems for enhancing the delivery of resveratrol. Annals of the New York Academy of Sciences, 1290(1), 107–112. Aung, H. H., Wang, C. Z., Ni, M., Fishbein, A., Mehendale, S. R., Xie, J. T., ... Yuan, C. S. (2007). Crocin from Crocus sativus possesses significant anti-proliferation effects on human colorectal cancer cells. Experimental Oncology, 29(3), 175. Belhaj, N., Dupuis, F., Arab-Tehrany, E., Denis, F. M., Paris, C., Lartaud, I., & Linder, M. (2012). Formulation, characterization and pharmacokinetic studies of coenzyme Q10 PUFA’s nanoemulsions. European Journal of Pharmaceutical Sciences, 47(2), 305–312. Boyd, B. J. (2008). Past and future evolution in colloidal drug delivery systems. Expert Opinion on Drug Delivery, 5(1), 69–85. Brandl, M. (2001). Liposomes as drug carriers: A technological approach. Biotechnology Annual Review, 7, 59–85. Brower, V. (1998). Nutraceuticals: Poised for a healthy slice of the healthcare market? Nature Biotechnology, 16, 728–732. Campardelli, R., & Reverchon, E. (2015). α-Tocopherolnanosuspensions produced using a supercritical assisted process. 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(2013). Nanoencapsulation techniques for food bioactive components: A review. Food and Bioprocess Technology, 6, 628–647. Fang, M., Jin, Y., Bao, W., Gao, H., Xu, M., Wang, D., & Liu, L. (2011). In vitro characterization and in vivo evaluation of nanostructured lipid curcumin carriers for intragastric administration. International Journal of Nanomedicine, 7, 5395–5404. Fathi, M., Mozafari, M. R., & Mohebbi, M. (2012). Nanoencapsulation of food ingredients using lipid based delivery systems. Trends in Food Science & Technology, 23(1), 13–27. Fernández-Romero, A. M., Maestrelli, F., Mura, P., Rabasco, A., & González-Rodríguez, M. (2018). Novel Findings about Double-Loaded Curcumin-in-HPβcyclodextrin-in Liposomes: Effects on the Lipid Bilayer and Drug Release. Pharmaceutics, 10(4), 256. Flanagan, J., & Singh, H. (2006). Microemulsions: A potential delivery system for bioactives in food. Critical Reviews in Food Science and Nutrition, 46(3), 221–237. Frede, K., Ebert, F., Kipp, A. 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4. Conclusion and future prospects Challenges in nutraceuticals involve their high dose levels, inadequate consistency and reproducibility, characterization and solubility problems, formulation challenges, stability issues at least over two years, and manufacturing issues on large scale for high-quality products. Further, much needs to be accomplished using nanonutraceuticals of biotechnologically-developed, genetically-modified, and tissue cultured products, and to find ways and manners to prove the efficiency of these products vis-à-vis those from naturally grown sources. Nanotechnology has vast applications in food industry. Study suggest that nanotechnology will provide the next new wave of food products, with promises of food that can adjust its color, flavor, or nutrient content to accommodate each person’s taste or health needs. Application of nanotechnology will address several of such challenges currently being faced by nutraceuticals. It has immense promise to reduce their dose levels and to result in better and longer stability to the nutraceuticals. The formulations of the bioactive as nanostructured products will help in their superior characterization, improved patient acceptability, and, above all, high reproducibility of their therapeutic effectiveness. A lot of nutraceutical products in nano sized forms are commercially available in the market. In addition to enhanced absorption, it is possible that nanosized nutraceuticals will have better bioavailability profile. For this reason we conclude that nano based carrier systems provide better means for enhancing the efficacy and availability of nutraceuticals having issues with solubility, stability and bioavailability. Ethical statement This is a review work and does not contain experiments on animals Declaration of Competing Interest All the authors declare no conflict of interest Acknowledgements The authors are thankful to Honourable Chancellor, Integral University, Lucknow for providing the necessary resources for successful completion of this work. References Aadinath, W., Bhushani, A., & Anandharamakrishnan, C. (2016). Synergistic radical scavenging potency of curcumin-in-β-cyclodextrin-in-nanomagnetoliposomes. Materials Science and Engineering: C, 64, 293–302. Acosta, E. (2000). Bioavailability of nanoparticles in nutrient and nutraceuticals delivery. Current Opinion in Colloid & Interface Science, 14(1), 3–15. Aditya, N. P., Yang, H., Kim, S., & Ko, S. (2015). Fabrication of amorphous curcumin nanosuspensions using β-lactoglobulin to enhance solubility, stability, and bioavailability. Colloids and Surfaces B: Biointerfaces, 127, 114–121. Ahmad, U., Akhtar, J., Singh, S. P., Badruddeen, Ahmad, F. J., Siddiqui, S., & Wahajuddin (2017). Silymarin nanoemulsion against human hepatocellular carcinoma: Development and optimization. Artificial Cells, Nanomedicine, and Biotechnology, 1–11. Ahmad, U., Faiyazuddin, M., Hussain, M. T., Ahmad, S., Alshammari, T. M., & Shakeel, F. (2015). Silymarin: An insight to its formulation and analytical prospects. Acta Physiologiae Plantarum, 37(11), 1–17. Ali, A., Ansari, V. A., Ahmad, U., Akhtar, J., & Jahan, A. (2017). Nanoemulsion: An advanced vehicle for efficient drug delivery. Drug Research, 67(11), 617–631. Ames, B. N., Shigenaga, M. K., & Hagen, T. M. (1993). Oxidants, antioxidants, and the

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